Drugs Used in Disorders of Coagulation PDF

Drugs Used in Disorders of Coagulation PHARMACOLOGY I (PLC 301)  Drugs Used in Disorders of Coagulation  Hemostasis refers to the finely regulated dynamic process of maintaining fluidity of the blood, repairing vascular injury, and limiting blood loss while avoiding ve...

Drugs Used in Disorders of Coagulation PHARMACOLOGY I (PLC 301)  Drugs Used in Disorders of Coagulation  Hemostasis refers to the finely regulated dynamic process of maintaining fluidity of the blood, repairing vascular injury, and limiting blood loss while avoiding vessel occlusion (thrombosis) and inadequate perfusion of vital organs.  Either extreme excessive bleeding or thrombosis represents a breakdown of the hemostatic mechanism.  Common causes of dysregulated hemostasis include : ✓ Hereditary or acquired defects in the clotting mechanism. ✓ Secondary effects of infection or cancer.  Causes of Normal Clot VS Unwanted thrombus Formation Physical trauma to the vascular system, such as a puncture or a cut: ✓ Initially, there is vasospasm of the damaged blood vessel to prevent further blood loss. ✓ Initiates a complex series of interactions between platelets, endothelial cells, and the coagulation cascade. ✓ These interactions lead to hemostasis or the cessation of blood loss from a damaged blood vessel.  Causes of Normal Clot VS Unwanted thrombus Formation ❑ The creation of an unwanted thrombus involves many of the same steps as normal clot formation, except that the triggering stimulus is a pathologic condition in the vascular system, rather than external physical trauma.  Thrombus VS Embolus “Thrombus”  A clot that adheres to a vessel wall. ✓ Venous thrombosis is usually associated with stasis of blood; thrombus has a small platelet component and a large component of fibrin. ✓ They contain large numbers of trapped RBCs. ✓ (Red thrombi). ✓ Arterial thrombosis is usually associated with atherosclerosis rendering arteries thrombogenic, and the thrombus has a large platelet component in a fibrin mesh. ✓ (White thrombi).  Thrombus VS Embolus “Thrombus”  A clot that adheres to a vessel wall. “Embolus”  An intravascular clot that floats in the blood. Both thrombi and emboli are dangerous, because they may occlude blood vessels and deprive tissues of oxygen and nutrients.  Resting platelets: Prostacyclin (also known as prostaglandin I2) is synthesized by intact endothelial cells and acts as an inhibitor of platelet aggregation. Prostacyclin binds to platelet membrane receptors that are coupled to the synthesis of cyclic adenosine monophosphate (cAMP), an intracellular messenger. Elevated levels of intracellular cAMP are associated with a decrease in intracellular calcium. Decreased intracellular calcium prevents platelet activation and the subsequent release of platelet aggregation agents.  Steps of Blood clot formation 1-Platelet adhesion When the endothelium is injured, platelets adhere to and virtually cover the exposed collagen of the subendothelium.  2- Platelet activation: ✓ Receptors on the surface of the adhering platelets are activated by the collagen of the underlying connective tissue. ✓ This causes morphologic changes in platelets and the release of platelet granules containing chemical mediators, such as adenosine diphosphate (ADP), thromboxane A2, serotonin, and platelet activation factor (PAF).  3- Platelet aggregation: ✓ These signaling molecules bind to receptors in the outer membrane of resting platelets circulating nearby. This results in elevated levels of calcium and a decreased concentration of cAMP within the platelet. Decreased cAMP Increased Ca+2 3- Platelet aggregation: 4-Formation of blood clot: Coagulation pathways: Both the extrinsic and the intrinsic systems involve a cascade of enzyme reactions that sequentially Factor III Factor III a transform various plasma factors (proenzymes) to their active (enzymatic) forms. [Note: The active form of a clotting factor is denoted by the letter “a.”] Thrombin plays a key role in coagulation, because it is responsible for generation of fibrin, which forms the mesh-like matrix of the blood clot. Factor I Active Factor Ia  5- Fibrinolysis:  During clot formation, the fibrinolytic pathway is locally activated. Plasminogen is enzymatically processed to plasmin (fibrinolysin) by tissue plasminogen activators (t-PA).  Plasmin limits the growth of the clot and dissolves the fibrin network as wounds heal. Tissue plasminogen activators  Anti-platelet A. Aspirin B. P2Y12 receptor antagonists: Examples: Ticlopidine, clopidogrel, ticagrelor (Oral) and cangrelor (IV). C. Glycoprotein IIb/IIIa inhibitors: Examples: Abciximab, Eptifibatide, Tirofiban D. Dipyridamole E. Cilostazol  1- Platelet aggregation inhibitors A. Aspirin 1. Mechanism of action:  Aspirin causes irreversible inactivation of COX-1 enzyme inhibiting thromboxane A2 synthesis thus inhibiting platelet aggregation.  1- Platelet aggregation inhibitors A. Aspirin 2. Therapeutic use: ✓ Pain relief, anti-inflammatory, fever reduction (Dose: 325 mg daily). ✓ Prevention of Blood Clots (Dose:75 or 81 mg daily) 1- Low-dose aspirin is commonly prescribed to prevent heart attacks, strokes, and other cardiovascular events in individuals at high risk. 2- It is used to prevent blood clots in patients undergoing surgery, particularly after joint replacement.  1- Platelet aggregation inhibitors A. Aspirin 3. Adverse effects: Bleeding time is prolonged by aspirin treatment, causing complications that include an increased incidence of hemorrhagic stroke and gastrointestinal (GI) bleeding, especially at higher doses of the drug. 4. Interactions:  Nonsteroidal anti- inflammatory drugs (NSAIDs), such as ibuprofen, inhibit COX-1 by transiently competing at the catalytic site.  Ibuprofen, if taken within 2 hours prior to aspirin, can obstruct the access of aspirin to the serine residue and, thereby, antagonize platelet inhibition by aspirin.  Therefore, immediate-release aspirin should be taken at least 60 minutes before or at least 8 hours after ibuprofen.  1- Platelet aggregation inhibitors B. P2Y12 receptor antagonists: Examples: Ticlopidine, clopidogrel, ticagrelor (Oral) and cangrelor (IV). 1. Mechanism of action:  These drugs inhibit the binding of ADP to the P2Y12 receptor on platelets and, thereby, inhibit the activation of the GP IIb/IIIa receptors required for platelets to bind to fibrinogen and to each other.  Ticagrelor and cangrelor bind to the P2Y12 ADP receptor in a reversible manner. The other agents bind irreversibly.  1- Platelet aggregation inhibitors B. P2Y12 receptor antagonists: 2. Therapeutic use: ✓ Clopidogrel is approved for prevention of atherosclerotic/ thrombotic events in patients with a recent MI or stroke and in case of percutaneous coronary intervention (PCI) with or without coronary stenting. ✓ Ticlopidine is generally reserved for patients who are intolerant to other therapies due to life- threatening hematologic adverse reactions. ✓ Ticagrelor is approved for the prevention of arterial thromboembolism in patients with unstable angina and acute MI, including those undergoing PCI. ✓ Cangrelor is approved as an adjunct during PCI to reduce thrombotic events.  1- Platelet aggregation inhibitors B. P2Y12 receptor antagonists: 3. Adverse effects:  Ticlopidine is associated with severe hematologic reactions that limit its use, such as agranulocytosis, thrombotic thrombocytopenic purpura (TTP), and aplastic anemia.  Clopidogrel causes fewer adverse reactions, and the incidence of neutropenia is lower.  Ticagrelor, and cangrelor carry black box warnings for bleeding.  Additionally, ticagrelor carries a black box warning for diminished effectiveness with concomitant use of aspirin doses above 100 mg. thrombotic thrombocytopenic purpura (TTP),  1- Platelet aggregation inhibitors C. Glycoprotein IIb/IIIa antagonists: Examples: abciximab, eptifibatide, tirofiban 1. Mechanism of action: ✓ Abciximab, eptifibatide and tirofiban bind to GP IIb/IIIa, blocking the binding of fibrinogen and consequently, aggregation does not occur.  1- Platelet aggregation inhibitors C. Glycoprotein IIb/IIIa inhibitors: 2. Therapeutic use: ✓ These agents are given IV, along with heparin and aspirin, as an adjunct to PCI for the prevention of cardiac ischemic complications. ✓ Abciximab is also approved for patients with unstable angina not responding to conventional medical therapy when PCI is planned within 24 hours. 3. Adverse effects: ✓ bleeding, especially if used with anticoagulants.  1- Platelet aggregation inhibitors D. Dipyridamole: 1. Mechanism of action: ✓ Dipyridamole, a coronary vasodilator, as it inhibits phosphodiesterase enzyme, increasing the intracellular levels of cAMP, along with decreasing ca+2 level, thereby resulting in decreased platelet activation and thromboxane A2 synthesis. ✓ The drug may potentiate the effect of prostacyclin and, therefore, decrease platelet adhesion to thrombogenic surfaces.  1- Platelet aggregation inhibitors D. Dipyridamole: 2. Therapeutic uses: ✓ Dipyridamole is used for stroke prevention and is usually given in combination with aspirin. ✓ Patients with unstable angina should not use dipyridamole because of its vasodilating properties, which may worsen ischemia (coronary steal phenomenon).  1- Platelet aggregation inhibitors D. Dipyridamole: 3. Adverse effects: ✓ Dipyridamole commonly causes headache and dizziness and can lead to orthostatic hypotension (especially if administered IV).  1- Platelet aggregation inhibitors E. Cilostazol 1. Mechanism of action: ✓ Cilostazol is an oral antiplatelet agent that possess the same mechanism of action as dipyridamole. 2. Therapeutic uses: ✓ Cilostazol is approved to reduce the symptoms of intermittent claudication.  1- Platelet aggregation inhibitors E. Cilostazol 3. Adverse effects:  Headache and GI side effects (diarrhea, abnormal stools, dyspepsia, and abdominal pain) are the most common adverse effects observed with cilostazol.  Rarely, thrombocytopenia or leukopenia has been reported.  Phosphodiesterase type III inhibitors have been shown to increase mortality in patients with advanced heart failure. As such, cilostazol is contraindicated in patients with heart failure. Why?????????????????  Anti-coagulants 1-Parenteral Anticoagulants a-Heparin and LMWHs (enoxaparin, dalteparin, and tinzaparin). b-Fondaparinux. c-Direct thrombin inhibitors (Argatroban, bivalirudin, desirudin and lepirudin). 2- Oral Anticoagulants a-Vitamin K Antagonists (warfarin, dicumarol) b-Direct thrombin inhibitors (Dabigatran) c-Direct oral factor Xa inhibitors (Apixaban, betrixaban, edoxaban, and rivaroxaban) Inhibitors of coagulation Endogenously, there are several inhibitors of coagulation factors, including: Parenteral Anticoagulants 1- Heparin (Unfractionated heparin) and low molecular weight heparins (LMWHs) ✓Heparin inhibits coagulation, both in vivo and in vitro. ✓ Heparin is an injectable (Subcutaneous /IV), rapidly acting anticoagulant that is often used acutely. ✓Heparin occurs naturally as mucopolysaccharides (sulfated glycosaminoglycans) complexed with histamine in mast cells, where its physiologic role is unknown. It is extracted for commercial use from porcine intestinal mucosa or beef lung. ✓Low molecular weight forms of heparin (LMWHs) possess anticoagulant effect and, they are produced by depolymerization of unfractionated heparin (one-third the size of unfractionated heparin). Parenteral Anticoagulants 1- Heparin (Unfractionated heparin) & low molecular weight heparins (LMWHs) Mechanism of action: ✓ Heparin binds to anti-thrombin III causing a conformational change that can increase the catalytic action of AT-III 1000-fold. ✓ Heparin potentiates its inactivation of factor Xa and thrombin. ✓ LMWHs complex with anti-thrombin III and increase the action of anti-thrombin III more selectively on factor Xa, with less effect on thrombin. Parenteral Anticoagulants 1- Heparin (Unfractionated heparin) and low molecular weight heparins (LMWHs) Therapeutic uses: ✓ Heparin and the LMWHs (such as enoxaparin, dalteparin, and tinzaparin) limit the expansion of established thrombi by preventing fibrin formation. ✓ Prevention of thrombosis. ✓ These drugs are the anticoagulants of choice for treating pregnant women (why????), because they do not cross the placenta, due to their large size and negative charge. ✓ The unfractionated product being reserved for special situations such as patients with severe renal failure in whom LMWHs are contraindicated. Parenteral Anticoagulants 1- Heparin (Unfractionated heparin) & low molecular weight heparins (LMWHs) Adverse effects: ✓ The chief complication of heparin and LMWH therapy is bleeding. managed by: ❑ stopping the drug ❑ giving fresh frozen plasma to provide coagulation factors ❑ treating with protamine sulfate (positive charge that binds to negatively charged heparin to form stable complex). ✓Hypersensitivity reactions: Heparin preparations are obtained from animal sources and, therefore, may be antigenic. Possible adverse reactions include chills, fever, urticaria, and anaphylactic shock. ✓Osteoporosis has been observed in patients on long-term heparin therapy. Parenteral Anticoagulants 1- Heparin (Unfractionated heparin) and low molecular weight heparins (LMWHs) Adverse effects: ✓ Heparin-induced thrombocytopenia (HIT) is a systemic hypercoagulable serious state that occurs in 1–4% of individuals treated with UFH. This reaction is immune mediated and carries a risk of venous and arterial embolism. ❑ Heparin therapy should be discontinued when patients develop HIT or show severe thrombocytopenia. ❑ In cases of HIT, heparin can be replaced by another anticoagulant, such as argatroban. ❑ [Note: LMWHs can have cross-sensitivity and are not recommended in patients with HIT.]  Parenteral Anticoagulants b- Fondaparinux: Mechanism of action:  Fondaparinux is an anticoagulant that selectively inhibits factor Xa. By selectively binding to anti-thrombin III.  Parenteral Anticoagulants b- Fondaparinux: Side effects: ❑ Bleeding is the major side effect of fondaparinux. There is no available agent for the reversal of bleeding associated with fondaparinux. ❑ HIT is less likely with fondaparinux than with heparin but is still a possibility. ❑ It is contraindicated in patients with severe renal impairment.  Parenteral Anticoagulants c- Direct thrombin(Factor II) inhibitors: ✓ Argatroban, bivalirudin, desirudin and lepirudin ✓ Argatroban, given by continuous IV infusion, is used for the prophylaxis or treatment of VTE in patients with HIT, and it is also approved for use during (PCI) in patients who have or are at risk for developing HIT. Anticoagulant effects are immediate. ✓ Bivalirudin is an alternative to heparin in patients undergoing PCI who have or are at risk for developing HIT and also in patients with unstable angina undergoing angioplasty. ✓ Desirudin is indicated for the prevention of DVT in patients undergoing hip replacement surgery. ✓ Lepirudin is used for thromboembolic disease in patients with type II HIT. ✓ Like the others, bleeding is the major side effect of direct thrombin inhibitors.  Oral Anticoagulants a- Vitamin K Antagonists (Coumarin anticoagulants) ✓ Examples: Warfarin, Dicumarol ✓ Vitamin K antagonists act only in vivo and have no effect on clotting if added to blood in vitro. ✓ They have a narrow therapeutic index. ✓ Dicumarol is a naturally occurring anticoagulant with much less well absorption and increases the potential for bleeding episodes.  Oral Anticoagulants a- Vitamin K Antagonists (Coumarin anticoagulants) ✓ Their effect is monitored by measuring the international normalized ratio (INR) and the dose is individualized (adjusted) accordingly. ✓ Therefore, it is important that the INR is maintained within the optimal range for prophylaxis and treatment of thrombotic disease (2–3) as much as possible, and frequent monitoring may be required.  Oral Anticoagulants a- Vitamin K Antagonists (Coumarin anticoagulants) Warfarin 1- Mechanism of action: Factors II (prothrombin), VII, IX and X  Oral Anticoagulants a- Vitamin K Antagonists (Coumarin anticoagulants) Warfarin NOTE: ✓ Unlike heparin, the anticoagulant effects of warfarin are not observed immediately after drug administration. Instead, peak effects take several days to develop (72 to 96 hours), which is the time required for degradation of preformed carboxylated clotting factors. ✓ For this reason, in patients with active hypercoagulable states, such as acute DVT or PE: ✓ UFH or LMW heparin is always used concurrently with warfarin to achieve immediate anticoagulation. The duration of this overlapping therapy is generally 5–7 days.  Oral Anticoagulants a- Vitamin K Antagonists (Coumarin anticoagulants) Warfarin 2- Therapeutic uses: Warfarin is used in the prevention and treatment of: ✓ Deep venous thrombosis (DVT) ✓ Post-operative thrombosis ✓ Cerebral venous thrombosis ✓ Coronary thrombosis ✓ Acute arterial and pulmonary embolism. ✓ Atrial fibrillation and artificial heart valve  Oral Anticoagulants a- Vitamin K Antagonists (Coumarin anticoagulants) Warfarin 3- Drug interactions: ✓ Drugs that inhibit hepatic P450 enzymes. Metronidazole, fluconazole, cotrimoxazole, amiodarone, and cimetidine inhibit the metabolic transformation of warfarin and increase drug activity. ✓ Aspirin augments warfarin’s effects by inhibiting platelet function and displacement of warfarin from plasma-binding sites. ✓ Drugs that have a greater affinity for the albumin-binding site, such as sulfonamides, can displace warfarin and lead to a transient, elevated activity.  Oral Anticoagulants a- Vitamin K Antagonists (Coumarin anticoagulants) Warfarin 3- Drug interactions: ✓ Drugs that induce hepatic P450 enzymes. Barbiturates, carbamazepine and rifampin cause a marked decrease of the anticoagulant effect. ✓ Drugs that reduce absorption. Cholestyramine binds warfarin in the intestine and reduces its absorption and bioavailability. ✓ Pharmacodynamic reductions of anticoagulant effect occur with increased vitamin K intake (increased synthesis of clotting factors).  Oral Anticoagulants a- Vitamin K Antagonists (Coumarin anticoagulants) Warfarin 4- Adverse effects: ✓ The principal adverse effect of warfarin is bleeding. ❑ Minor bleeding may be treated by withdrawal of the drug or administration of oral vitamin K. ❑ Severe (life-threatening) bleeding may require greater doses of vitamin K(IV) +Whole blood, fresh-frozen plasma, may also be used for rapid reversal of warfarin. ✓ Skin lesions and cutaneous necrosis with reduced activity of protein C are rare complications of warfarin therapy.  Oral Anticoagulants a- Vitamin K Antagonists (Coumarin anticoagulants) Warfarin 4- Adverse effects: ✓ Warfarin is contraindicated in pregnancy and is not given in the first months of pregnancy because it is teratogenic causing disordered bone development, nor in the later stages because it can cause intracranial hemorrhage in the baby during delivery. ✓ Purple toe syndrome, a rare, painful, blue-tinged discoloration of the toe caused by cholesterol emboli from plaques  Oral Anticoagulants b- Direct thrombin inhibitor: Dabigatran 1- Mechanism of action: ✓ Dabigatran is, an oral direct thrombin inhibitor. ✓ Both clot-bound thrombin and free thrombin are inhibited by dabigatran.  Oral Anticoagulants b- Direct thrombin inhibitor: Dabigatran 2- Adverse effects: ✓ Bleeding. ❑ Idarucizumab may be used to reverse bleeding in severe cases; the drug is approved for use in situations requiring emergent surgery or for life-threatening bleeding. ✓ GI adverse effects are common with dabigatran and may include dyspepsia, abdominal pain, esophagitis, and GI bleeding. ✓ Abrupt discontinuation should be avoided, as patients may be at increased risk for thrombotic events.  Oral Anticoagulants c- Direct oral factor Xa inhibitors Apixaban, betrixaban, edoxaban, and rivaroxaban 1- Mechanism of action: ✓ They are oral inhibitors of factor Xa that reduce the production of factor IIa from prothrombin.  Oral Anticoagulants c- Direct oral factor Xa inhibitors Apixaban, betrixaban, edoxaban, and rivaroxaban 2- Adverse effects: ✓ Bleeding is the most serious adverse effect. ✓ Andexanet alfa is a factor Xa “decoy” molecule without procoagulant activity that competes for binding to anti-Xa drugs. It is the first antidote approved for use in patients treated with anti-Xa agents who require rapid reversal for surgery or uncontrolled bleeding.